U.S. patent application number 11/558132 was filed with the patent office on 2007-05-24 for anthranilamides and methods of their use.
This patent application is currently assigned to sanofi-aventis Deutschland GmbH. Invention is credited to Joachim Brendel, Horst Hemmerle, Heinz-Werner Kleemann, Stefan Peukert, Bernard Pirard.
Application Number | 20070117807 11/558132 |
Document ID | / |
Family ID | 7683152 |
Filed Date | 2007-05-24 |
United States Patent
Application |
20070117807 |
Kind Code |
A1 |
Brendel; Joachim ; et
al. |
May 24, 2007 |
ANTHRANILAMIDES AND METHODS OF THEIR USE
Abstract
The present invention is related to a process for preparing
anthranilamides of formula I, ##STR1## in which R(1) to R(7) have
the meanings indicated herein, a process for their preparation,
their use as medicaments, and pharmaceutical preparations
containing them. The compounds act on the Kv1.5 potassium channel
and inhibit a potassium current which is referred to as the
ultra-rapidly activating delayed rectifier in the atrium of the
human heart. The compounds are therefore suitable for use as novel
antiarrhythmic agents for the treatment and prophylaxis of atrial
arrhythmias (e.g., atrial fibrillation (AF) or atrial flutter).
Inventors: |
Brendel; Joachim; (Bad
Vilbel, DE) ; Pirard; Bernard; (Frankfurt, DE)
; Peukert; Stefan; (Frankfurt, DE) ; Kleemann;
Heinz-Werner; (Bischofsheim, DE) ; Hemmerle;
Horst; (Indianapolis, IN) |
Correspondence
Address: |
ROSS J. OEHLER;SANOFI-AVENTIS U.S. LLC
1041 ROUTE 202-206
MAIL CODE: D303A
BRIDGEWATER
NJ
08807
US
|
Assignee: |
sanofi-aventis Deutschland
GmbH
Frankfurt am Main
DE
|
Family ID: |
7683152 |
Appl. No.: |
11/558132 |
Filed: |
November 9, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10132163 |
Apr 26, 2002 |
|
|
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11558132 |
Nov 9, 2006 |
|
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Current U.S.
Class: |
514/252.03 ;
514/255.05; 514/255.06; 514/275; 544/238; 544/331; 544/405;
544/406 |
Current CPC
Class: |
C07D 405/12 20130101;
C07D 213/64 20130101; C07D 231/12 20130101; C07D 307/14 20130101;
C07D 207/335 20130101; C07D 307/52 20130101; C07D 235/14 20130101;
C07D 233/64 20130101; C07C 2601/02 20170501; C07D 277/28 20130101;
C07D 215/12 20130101; C07D 213/40 20130101; A61P 9/06 20180101;
C07C 311/08 20130101; C07D 231/16 20130101; C07C 311/29 20130101;
C07C 311/44 20130101; C07D 233/56 20130101; C07C 311/21 20130101;
C07C 2601/14 20170501; C07D 249/08 20130101 |
Class at
Publication: |
514/252.03 ;
514/255.05; 514/255.06; 514/275; 544/238; 544/331; 544/405;
544/406 |
International
Class: |
A61K 31/501 20060101
A61K031/501; A61K 31/4965 20060101 A61K031/4965; A61K 31/497
20060101 A61K031/497; C07D 403/02 20060101 C07D403/02 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 28, 2001 |
DE |
10121003.5 |
Claims
1-18. (canceled)
19. A process for preparing a compound of formula I, ##STR235##
##STR236## in which: A --C.sub.nH.sub.2n--; n is 0, 1, 2, 3, 4 or
5; O is oxygen; D is a bond or oxygen; E is --C.sub.mH.sub.2m--; m
is 0, 1, 2, 3, 4 or 5; R(8) is hydrogen, alkyl having 1, 2, 3 or 4
carbon atoms or C.sub.pH.sub.2p--R(14); p is 0, 1, 2, 3, 4 or 5;
R(14) is cyoloalkyl having 3, 4, 5 or 6 carbon atoms, aryl or
heteroaryl, where aryl and heteroaryl are unsubstituted or
substituted by 1, 2 or 3 substituents selected from the group
consisting of F, Cl, Br, I, CF.sub.3, OCF.sub.3, NO.sub.2, CN,
COOMe, CONH.sub.2, COMe, NH.sub.2, OH, alkyl having 1, 2, 3 or 4
carbon atoms alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino
sulfamoyl, methylsulfonyl and methylsulfonylamino; R(9) is hydrogen
or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; R(10) is hydrogen,
alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5
or 6 carbon atoms, aryl or heteroaryl, where aryl, and heteroaryl
are unsubstituted or substituted by 2 or 3 substituents selected
from the group consisting of F, Cl, Br, I, CF.sub.3, OCF.sub.3,
NO.sub.2, CN, COOMe, CONH.sub.2, COMe, NH.sub.2, OH, alkyl having
1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms,
dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R(11) is cycloalkyl having 3, 4, 5 or 6 carbon atoms, phenyl,
naphthyl, thienyl, furyl, pyridyl, pyrazinyl, pyridazinyl, or
pyrimidyl, where phenyl, naphthyl, thienyl, furyl, pyridyl,
pyrazinyl, pyridazinyl and pyrimidyl are unsubstituted or
substituted by 1, 2 or 3 substituents selected from the group
consisting of F, Cl, Br, I, CF.sub.3, OCF.sub.3, NO.sub.2, CN,
COMe, NH.sub.2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy
having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl,
methylsulfonyl and methylsulfonylamino; R(12) alkyl having 1, 2, 3
or 4 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms aryl
or heteroaryl, where aryl and heteroaryl are unsubstituted or
substituted by 1, 2 or 3 substituents selected from the group
consisting of F, Cl, Br, I, CF.sub.3, CO.sub.3, NO.sub.2, CN,
COOMe, ONH.sub.2, COMe, NH.sub.2, OH, alkyl having 1, 2, 3 or 4
carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms,
dimethylamino, sulfamoyl, methylulfonyl and methylsulfonylamino;
R(13) is C.sub.pH.sub.2p--R'(14); p is 0, 1, 2, 3, 4 or 5; R'(14)
is cycloakyl having 3, 4, 5 or 6 carbon atoms tetrahydrofuranyl,
tetrahydropyranyl, aryl or heteroaryl, where aryl and heteroaryl
are unsubstituted or substituted by 1, 2 or 3 substituents selected
from the group consisting of F, Cl, Br, I, CF.sub.3, OCF.sub.3,
NO.sub.2, CN, COOMe, CONH.sub.2, COMe, NH.sub.2, OH, alkyl having
1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms,
dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino,
R(15) is cycoalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms; R(2) is
hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms R(3) is alkyl
having 3, 4, 5, 6 or 7 carbon atoms atoms, cycloalkyl having 3, 4,
5 and 6 carbon atoms, phenyl or naphthyl, where phenyl or naphthyl
are unsubstituted of substituted by 1, 2 or 3 substituents selected
from the group consisting of F, Cl, Br, I, CF.sub.3, OCF.sub.3,
NO.sub.2, CN, COOMe, CONH.sub.2, NH.sub.2, OH, alkyl having 1, 2, 3
or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms,
dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
and R(4), R(5), R(6) and R(7) are, independently of one another,
selected from the group consisting of hydrogen, F, Cl, Br, I,
CF.sub.3, OCF.sub.3, OCHF.sub.2, NO.sub.2, CN, COOMe, CONH.sub.2,
COMe, NH.sub.2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, a
alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl,
methylsulfonyl and or a pharmaceutically acceptable salt thereof,
which comprises, ##STR237## a) reacting an aminocarboxylic acid of
formula II with a sulfonyl chloride of formula R(3)-SO.sub.2--Cl or
a sulfonic acid anhydride in the presence of a base, and b)
reacting the resulting sulfonylaminocarboxylic acid of formula III
with an amine of formula HR(1) to the compound of formula I, where,
in the compounds of the formulae II and III, R1 to R7 are each as
defined in formula I.
20. The process of claim 19, in which the base used in reaction
step a) is selected from the group of sodium carbonate potassium
hydroxide, pyridine and triethylamine.
21. The process of claim 19, in which the carboxylic acid group of
the compound of formula III is activated before by the reaction
with an amine of formula HR(1) in reaction step b).
22. The process of claim 21, in which the carboxylic acid group of
the compound of formula III is activated by converting it into an
acid chloride, a mixed anhydride or an activated ester.
23. The process of claim 19 wherein: ##STR238## A is
--C.sub.nH.sub.2n--; n is 0, 1 or 2; D is a bond or oxygen; E is
--C.sub.mH.sub.2m--; m is 0 or 1; R(8) is hydrogen or alkyl having
1, 2, 3 or 4 carbon atoms; R(9) is hydrogen or alkyl having 1, 2, 3
or 4 carbon atoms; R(11) is phenyl or pyridyl, where phenyl and
pyridyl are unsubstituted or substituted be 1, 2 or 3 substituents
selected from the group consisting of F, Cl, CF.sub.3, OCF.sub.3,
CN, COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having
1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl
and methylsulfonylamino R(12) is alkyl having 1, 2, 3 or 4 carbon
atoms or cyclopropyl; R(2) is hydrogen; R(3) alkyl having 3, 4 or 5
carbon atoms or phenyl, where phenyl is unsubstituted or
substituted by 1, 2 or 3 substituents selected from the group
consisting of F, Cl, CF.sub.3, OCF.sub.3, COOMe, CONH.sub.2, COMe,
OH, alkyl having 1, 2, 3 or 4 carbon atoms alkoxy having 1, 2, 3 or
4 carbon atoms, dimethylamino sulfamoyl, methylsulfonyl and
methylsulfonylamino; and R(4), R(5), R(6) and R(7) are,
independently of one another, selected from the group consisting of
hydrogen, F, Cl, CF.sub.3, OCF.sub.3, CN, COOSMe, CONH.sub.2, COMe,
OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3
or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and a
methylsulfonylamino.
24. A process for preparing a compound of formula I, ##STR239## in
which: ##STR240## A is --C.sub.nH.sub.2n--; n is 0, 1, 2, 3, 4 or
5; O is oxygen; D is a bond or oxygen; E is --C.sub.mH.sub.2m--; m
is 0, 1, 2, 3, 4 or 5; R(8) is hydrogen, alkyl having 1, 2, 3 or 4
carbon atoms or C.sub.pH.sub.2p--R(14); p is 0, 1, 2, 3, 4 or 5;
R(14) is cycloalkyl having 3, 4, 5 or 6 carbon atoms, aryl or
heteroaryl, where aryl and heteroaryl are unsubstituted or
substituted by 1, 2 or 3 substituents selected from the group
consisting of F, Cl, Br, I, CF.sub.3, OCF.sub.3, NO.sub.2, CN,
COOMe, CONH.sub.2, COMe, NH.sub.2, OH, alkyl having 1, 2, 3 or 4
carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms,
dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R(9) is hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atom;
R(10) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms,
cycloalkyl having 3, 4, 5 or 6 carbon atoms, aryl or heteroaryl,
where aryl and heteroaryl are unsubstituted or substituted by 1, 2
or 3 substituents selected from the group consisting of F, Cl, Br,
I, CF.sub.3, OCF.sub.3, NO.sub.2, CN, COOMe, CONH.sub.2, COMe,
NH.sub.2, OH, alkyl having 1, 2, 3 or 4 carbon atoms alkoxy having
1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl
and methylsulfonylamino; R(11) is cycloalkyl having 3, 4, 5 or 6
carbon atoms, phenyl, naphthyl, thienyl, furyl, pyridyl, pyrazinyl,
pyridazinyl or pyrimidyl, where phenyl, naphthyl, thienyl furyl,
pyridyl, pyrazinyl, pyridazinyl and pyrimidyl are unsubstituted or
substituted by 1, 2 or 3 substituents selected from the group
consisting of F, Cl, Br, I, CF.sub.3, OCF.sub.3, NO.sub.2, CN,
COMe, NH.sub.2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy
having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl,
methylsulfonyl and methylsulfonylamino; R(12) is alkyl having 1, 2,
3 or 4 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms,
aryl or heteroaryl, where aryl and heteroaryl are unsubstituted or
substituted by 1, 2 or 3 substituents selected from the group
consisting of F, Cl, Br, I, CF.sub.3, OCF.sub.3, NO.sub.2, CN,
COOMe, CONH.sub.2, COMe, NH.sub.2, OH, alkyl having 1, 2, 3 or 4
carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms,
dimethylamino, sulfamino, methylsulfonyl and methylsulfonylamino;
R(13) C.sub.pH.sub.2p--R'(14); p is 0, 1, 2, 3, 4 or 5; R'(14) is
cycloalkyl having 3, 4, 5 or 6 carbon atoms tetrahydrofuranyl,
tetrahydropyranyl, aryl or heteroaryl, where aryl and heteroaryl
are unsubstituted or substituted by 1, 2 or 3 substituents selected
from the group consisting of F, Cl, Br, I, CF.sub.3, OCF.sub.3,
NO.sub.2, CN, COOMe CONH.sub.2, COMe, NH.sub.2, OH, alkyl having 1,
2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms,
dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R(15) is cycloalkyl having 3, 4, 5, 7 or 8 carbon atoms; R(2) is
hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; R(3) is alkyl
having 3, 4, 5, 6 or 7 carbon atoms, cycloalkyl having 3, 4, 5 or 6
carbon atoms, phenyl or naphthyl, where phenyl or naphthyl are
unsubstituted of substituted by 1, 2 or 3 substituents selected
from the group consisting of F, Cl, Br, I, CF.sub.3, OCF.sub.3,
NO.sub.2, CN, COOMe, CONH.sub.2, COMe, NH.sub.2, OH, alkyl having
1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms,
dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
and R(4), R(5), R(6) and R(7) are, independently of one another,
selected from the group consisting of hydrogen, F, Cl, Br, I,
CF.sub.3, OCF.sub.3, OCHF.sub.2, NO.sub.2, CN, COOMe, CONH.sub.2,
COMe, NH.sub.2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy
having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl,
methylsulfonyl and methylsulfonylamino; or a pharmaceutically
acceptable salt thereof, which comprises, ##STR241## a) reacting an
anhydride of formula IV with an amine of formula H--R1, and b)
reacting the resulting o-aminobemzamide of formula VII with an
sulfonyl chloride of formula R(3)SO.sub.2Cl to obtain a compound of
formula I, where, in the compounds of the formulae II and III, R1
to R7 are each as defined in formula I.
25. The process of claim 24 wherein: ##STR242## A is
--C.sub.nH.sub.2n--; n is 0, 1 or 2; D is a bond or oxygen; E is
C.sub.mH.sub.2m--; m is 0 or 1; R(8) is hydrogen or alkyl having 1,
2, 3 or 4 carbon atoms; R(9) is hydrogen or alkyl having 1, 2, 3 or
4 carbon atoms; R(11) is phenyl or pyridyl, where phenyl, and
pyridyl are unsubstituted or substituted by 1, 2 or 3 substituents
selected from the group consisting of F, Cl, CF.sub.3, OCF.sub.3,
CN, COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having
1, 2, 3 or 4 carbon atoms, dimethylamino sulfamoyl, methylsulfonyl
and methylsulfonylamino; R(12) is alkyl having 1, 2, 3 or 4 carbon
atoms or cyclopropyl, R(2) is hydrogen; R(3) is alkyl having 3, 4
or 5 carbon atoms or phenyl where phenyl is unsubstituted or
substituted by 1, 2 or 3 substituents selected from the group
consisting of F, Cl, CF.sub.3, OCF.sub.3, COOMe, CONH.sub.2, COMe,
OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3
or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and
methylsulfonylamino; and R(4), R(5), R(6) and R(7) are,
independently of one another, selected from the group consisting of
hydrogen, F, Cl, CF.sub.3, OCF.sub.3, CN, COOMe, CONH.sub.2, COMe,
OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3
or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and
methylsulfonylamino.
26. A process for preparing a compound of formula I, ##STR243## in
which: ##STR244## A is --C.sub.nH.sub.2n--; n is 0, 1, 2, 3, 4 or
5; O is oxygen; D is a bond or oxygen; E is --C.sub.mH.sub.2m--; m
is 0, 1, 2, 3, 4 or 5; R(8) is hydrogen, alkyl having 1, 2, 3 or 4
carbon atoms or C.sub.pH.sub.2p--R(14); p is 0, 1, 2, 3, 4 or 5;
R(14) is cycloalkyl having 3, 4, 5 or 6 carbon atoms, aryl or
heteroaryl, where aryl and heteroaryl are unsubstituted or
substituted by 1, 2 or 3 substituents selected from the group
consisting of F, Cl, Br, I, CF.sub.3, OCF.sub.3, NO.sub.2, CN,
COOMe, CONH.sub.2, COMe, NH.sub.2, OH, alkyl having 1, 2, 3 or 4
carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms,
dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R(9) is hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms
R(10) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms,
cycloalkyl having 3, 4, 5 or 6 carbon atoms, aryl or heteroaryl,
where aryl and heteroaryl are unsubstituted or substituted by 1, 2
or 3 substituents selected from the group consisting of F, Cl, Br,
I, CF.sub.3, OCF.sub.3, NO.sub.2, CN, COOMe, CONH.sub.2, COMe,
NH.sub.2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having
1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl
and methylsulfonylamino; R(11) is cycloalkyl having 3, 4, 5 or 6
carbon atoms, phenyl, nephthyl, thienyl, furyl, pyridyl, pyrazinyl,
pyridazinyl or pyrimidyl, where phenyl, naphthyl, thienyl, furyl,
pyridyl, pyrazinyl, pyridazinyl and pyrimidyl are unsubstituted or
substituted by 1, 2 or 3 substituents selected from the group of F,
Cl, Br, I, CF.sub.3, OCF.sub.3, NO.sub.2, CN, COMe, NH.sub.2, OH,
alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4
carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and
methylsulfonylamino; R(12) is alkyl having 1, 2, 3 or 4 carbon
atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, aryl or
heteroaryl, where any and heteroaryl are unsubstituted or
substituted by 1, 2 or 3 substituents selected from the group
consisting of F, Cl, Br, CF.sub.3, OCF.sub.3, NO.sub.2, ON, COOMe,
CNOH.sub.2, COMe, NH.sub.2, OH, alkyl haring 1, 2, 3 or 4 carbon
atoms, alkoxy having 2, 2, 3 and methylsulfonylamino; R(13) is
C.sub.pH.sub.2p--R'(14) p is 0, 1, 2, 3, 4 or 5; R'(14) is
cycloalkyl having 3, 4, 5 or 6 carbon atoms tetrahydrofuranyl,
tetrahydropyranyl, aryl, or heteroaryl, where aryl and heteroaryl
are unsubstituted or substituted by 1, 2 or 3 substitutents
selected from the group consisting of F, Cl, Br, I, CF.sub.3,
OCF.sub.3, NO.sub.2, CN, COOMe, CONH.sub.2, COMe, NH.sub.2, OH,
alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4
carbon atoms, dimethylamino, sulfamoyl methylsulfonyl and
methylsulfonylamino; R(15) is cycloalkyl having 3, 4, 5, 6, 7 or 8
carbon atoms, R(2) is hydrogen; R(3) is alkyl having 3, 4, 5, 6 or
7 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, phenyl
or naphthyl, where phenyl or naphthyl are unsubstituted of
substituted by 1, 2 or 3 substituents selected from the group
consisting of F, Cl, Br, I, CF.sub.3, OCF.sub.3, NO.sub.2, CN,
COOMe, CONH.sub.2, COMe, NH.sub.2, OH, alkyl having 1, 2, 3 or 4
carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms,
dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino,
and R(4), R(5), R(6) and R(7) are, independently of one another,
selected from the group consisting of hydrogen, F, Cl, Br, I,
CF.sub.3, OCF.sub.3, OCHF.sub.2, NO.sub.2, CN, COOMe, CONH.sub.2,
COMe, NH.sub.2, OH, alkyl having 1, 2, 3 or 4 carbon atoms alkoxy
having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl,
methylsulfonyl and methylsulfonylamino; or a pharmaceutically
acceptable salt thereof, which comprises, ##STR245## a) amidation
of an o-nitrobenzoic acid of formula V with an amine of formula
HR(1), b) reducing the nitro group in the resulting compound of
formula VI to an amine of formula VII, and b) reacting the
resulting o-aminobemzamide of formula VII with an sulfonyl chloride
of formula R(3)SO.sub.2Cl to obtain a compound of formula I, where,
in the compounds of the formulae II and III, R1 to R7 are each as
defined in formula I.
27. The process of claim 26 wherein, ##STR246## A is
--C.sub.nH.sub.2n--; n is 0, 1 or 2; D is a bond or oxygen; E is
--C.sub.mH.sub.2m--; m is 0 or 1; R(8) is hydrogen or alkyl having
1, 2, 3 or 4 carbon atoms; R(9) is hydrogen or alkyl having 1, 2, 3
or 4 carbon atoms; R(11) is phenyl or pyridyl, where phenyl and
pyridyl are unsubstituted or substituted by 1, 2 or 3 substituents
selected from the group consisting of F, Cl, CF.sub.3, OCF.sub.3,
CN, COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having
1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl
and methylsulfonylamino; R(12) is alkyl having 1, 2, 3 or 4 carbon
atoms or cyclopropyl; R(2) is hydrogen; R(3) is alkyl having 3, 4
or 5 carbon atoms or phenyl, where phenyl is unsubstituted or
substituted by 1, 2 or 3 substituents selected from the group
consisting of F, Cl, CF.sub.3, OCF.sub.3, COOMe, CONH.sub.2, COMe,
OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3
or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and
methylsulfonylamino; and R(4), R(5), R(6) and R(7) are,
independently of one another, selected from the group consisting of
hydrogen, F, Cl, CF.sub.3, OCF.sub.3, CN, COOMe, CONH.sub.2, COMe,
OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3
or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and
methylsulfonylamino.
Description
[0001] The invention relates to compounds of formula I, ##STR2## in
which R(1), R(2), R(3), R(4), R(5), R(6) and R(7) have the meanings
indicated hereinafter, to their preparation and use, and in
particular, to their use as pharmaceuticals.
[0002] The compounds of formula I have not previously been
disclosed. They act on the Kv1.5 potassium channel in the atrium of
the human heart, which is referred to as ultra-rapidly activating
delayed rectifier, and inhibit the potassium current. The compounds
are therefore suitable as novel antiarrhythmic agents for the
treatment and prophylaxis of atrial arrhythmias, e.g., atrial
fibrillation (AF) or atrial flutter.
[0003] Atrial fibrillation (AF) and atrial flutter are the most
common and persistent cardiac arrhythmias. Their occurrence
increases with increasing age and frequently leads to other fatal
symptoms, such as stroke. AF affects about 1 million Americans each
year and leads to more than 80,000 strokes annually in the USA. The
class I and III antiarrhythmic agents in use at present reduce the
rate of AF occurrence, but can only be used in a limited manner due
to their proarrhythmic side effects. Consequently, there is a great
medical need to develop better medicaments for the treatment of
atrial arrhythmias (S. Nattel (1995) "Newer developments in the
management of atrial fibrillation," Am. Heart J.,
130:1094-1106).
[0004] It has been shown that most supraventricular arrhythmias are
subject to reentry waves. Such reentry waves occur when the cardiac
tissue exhibits slow conductivity and, at the same time, very short
refractory periods. Increasing the myocardial refractory period by
prolonging the action potential is an acknowledged mechanism for
terminating arrhythmias and preventing development of arrhythmic
conditions (T. J. Colatsky et al (1990), "Potassium channels as
targets for antiarrhythmic drug action," Drug Dev. Res.
19:129-140). The length of the action potential is essentially
determined by the extent of repolarizing K.sup.+ currents which
flow out of the cells through various K.sup.+ channels. The delayed
rectifier I.sub.K, which consists of 3 different components,
IK.sub.r, IK.sub.s and IK.sub.ur, plays an important role in this
process.
[0005] Most of the known class III antiarrhythmics (e.g.,
dofetilide, E4031 and d-sotalol) predominantly or exclusively block
the rapidly activating potassium channel IK.sub.r, which can be
detected both in cells of the human ventricle and in the atrium.
However, it has emerged that these compounds increase the risk of
arrhythmias at low or normal heart rates, in particular,
arrhythmias referred to as torsades de pointes (D. M. Roden (1993)
"Current status of class III antiarrhythmic drug therapy," Am. J.
Cardiol. 72:44B-49B). In addition to this increased risk, which can
be fatal, the efficacy of I.sub.Kr blockers declines at the lower
heart rates experienced during conditions of tachycardia, precisely
when the effective action of these blockers is needed most.
[0006] Whereas some of the disadvantages can possibly be overcome
by blockers of the slowly activating component (IK.sub.s), their
efficacy has not yet been proven because no clinical investigations
with IK.sub.s channel blockers are known.
[0007] The "ultra-rapidly" activating and very slowly deactivating
component of the delayed rectifier is termed IK.sub.ur
(=ultra-rapidly activating delayed rectifier). This corresponds to
the Kv1.5 channel, and plays a major role in the repolarization
time in the human atrium. Compared with the inhibition of IK.sub.r
or IK.sub.s, inhibition of the IK.sub.ur potassium outward current
is a more effective method for lengthening the atrial action
potential, thus terminating or preventing atrial arrhythmias.
Mathematical models of human action potential suggest that the
positive effects of blocking the IK.sub.ur should be particularly
pronounced under the pathological conditions of chronic atrial
fibrillation (M. Courtemanche, R. J. Ramirez, S. Nattel (1999)
"Ionic targets for drug therapy and atrial fibrillation-induced
electrical remodeling: insights from a mathematical model,"
Cardiovascular Research, 42:477-489).
[0008] In contrast to IK.sub.r and IK.sub.s, which occur in the
human ventricle, IK.sub.ur plays an important role in the human
atrium but not the ventricle. Thus, unlike IK.sub.r and IK.sub.s
blockers, the risk of a proarrhythmic effect from IK.sub.ur
blockers in the ventricle is not a concern (Z. Wang et al (1993)
"Sustained Depolarization-Induced Outward Current in Human Atrial
Myocytes," Circ. Res., 73:1061-1076; G. R. Li et al. (1996)
"Evidence for Two Components of Delayed Rectifier K.sup.+-Current
in Human Ventricular Myocytes," Circ. Res., 78:689-696; G. J. Amos
et al. (1996) "Differences between outward currents of human atrial
and subepicardial ventricular myocytes," J. Physiol.,
491:31-50).
[0009] However, antiarrhythmic agents which act via selective
blocking of the IK.sub.ur current or Kv1.5-channel have not been
commercially available to date. Although a blocking effect on the
Kv1.5 channel has been described for numerous pharmaceutical active
substances (e.g., tedisamil, bupivacaine or sertindole), the Kv1.5
block here is only a side effect to the intended main effects of
the substances.
[0010] WO 98 04 521 and WO 99 37 607 describe aminoindanes and
aminotetrahydrona-phthalenes as potassium channel blockers which
block the Kv1.5 channel. Structurally related aminochromanes are
likewise described as Kv1.5 blockers in WO 00 12 077. In WO 99 62
891, thiazolidinones which block the potassium channel are also
described. The applications WO 98 18 475 and WO 98 18 476 describe
the use of various pyridazinones and phosphine oxides as
antiarrhythmic agents which are said to act by blocking the
IK.sub.ur. However, the same compounds were known to be
immuno-suppressives (WO 96 25 936). All compounds described in
these publications are completely different structurally from the
presently disclosed compounds of the invention. Furthermore, the
present inventors are not aware of any clinical data for the
compounds disclosed in these publications. Since experience has
shown that only a small proportion of active substances from
preclinical research successfully overcome all clinical hurdles to
gain approval as medicaments, there is still a need in the art for
promising new compounds.
[0011] It has now been found, surprisingly, that the presently
disclosed anthranilamides of formula I are potent blockers of the
human Kv1.5 channel. These compounds can therefore be used as novel
antiarrhythmics with a particularly advantageous safety profile.
The compounds are particularly suitable for treating
supraventricular arrhythmias, e.g., atrial fibrillation or atrial
flutter.
[0012] The presently disclosed compounds can be employed for
terminating existing atrial fibrillation or flutter in order to
restore sinus rhythm (cardioversion). In addition, the substances
reduce the susceptibility to recurrence of further fibrillation
events (e.g., retention of sinus rhythm, prophylaxis).
[0013] The compounds of the invention have not previously been
disclosed. Some structurally related compounds are described in the
publications discussed hereinafter.
[0014] For example, compounds A and B, infra, were described in
FEBS Letters (1981) 421:217-220, as serine protease inhibitors.
Compounds C and D, infra, and similar derivatives, were described
in J. Med. Chem. (1968) 11:777-787, as precursors for the synthesis
of tetrahydroisoquino[2,1-d][1,4]benzodiazepines. ##STR3##
[0015] EP-A-686 625 describes anthranilic acid derivatives and
their use as cGMP phosphodiesterase inhibitors. Most of the 144
compounds described in this reference contain carbonyl groups,
which differ from the sulfonyl groups in the presently disclosed
compounds. Three of the examples provide a sulfonylamino
substituent (see, e.g., Example 131 in EP 686 625), which is
structurally similar to compound E, infra. However, the reference
provides no teaching or suggestion that such compounds function as
phosphodiesterase inhibitors or that they may be used as
antiarrhythmic agents. ##STR4##
[0016] EP-A-947 500 claims a large, heterogeneous group of
compounds which reportedly act as prostaglandin E2 antagonists or
agonists. Most of the described anthranilic acid derivatives
contain a free carboxylic acid function, thus differing from the
presently disclosed compounds.
[0017] European patent application EP-A 0 491 525 describes
anthranilamides with various 5-membered heterocycles in the side
chain, such as compound F, for treating diabetes. ##STR5##
[0018] These publications, however, provide no teaching or
suggestion that the disclosed compounds have a
K.sup.+-channel-blocking action and may be useful as medicaments
for the therapy and prophylaxis of K.sup.+-channel-mediated
diseases, such as arrhythmia.
[0019] The present invention relates to compounds of formula I,
##STR6## in which: ##STR7## [0020] A is --C.sub.nH.sub.2n--; [0021]
n is 0, 1, 2, 3, 4 or 5; [0022] O is oxygen; [0023] D is a bond or
oxygen; [0024] E is --C.sub.mH.sub.2m--; [0025] m is 0, 1, 2, 3, 4
or 5; [0026] R(8) is hydrogen, alkyl having 1, 2, 3 or 4 carbon
atoms or C.sub.pH.sub.2p--R(14); [0027] p is 0, 1, 2, 3, 4 or 5;
[0028] R(14) is cycloalkyl having 3, 4, 5 or 6 carbon atoms, aryl
or heteroaryl, where aryl and heteroaryl are unsubstituted or
substituted by 1, 2 or 3 substituents selected from the group
consisting of F, Cl, Br, I, CF.sub.3, OCF.sub.3, NO.sub.2, CN,
COOMe, CONH.sub.2, COMe, NH.sub.2, OH, alkyl having 1, 2, 3 or 4
carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms,
dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
[0029] R(9) is hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon
atoms; [0030] R(10) is hydrogen, alkyl having 1, 2, 3 or 4 carbon
atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, aryl or
heteroaryl, [0031] where aryl and heteroaryl are unsubstituted or
substituted by 1, 2 or 3 substituents selected from the group
consisting of F, Cl, Br, I, CF.sub.3, OCF.sub.3, NO.sub.2, CN,
COOMe, CONH.sub.2, COMe, NH.sub.2, OH, alkyl having 1, 2, 3 or 4
carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms,
dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
[0032] R(11) is cycloalkyl having 3, 4, 5 or 6 carbon atoms,
phenyl, naphthyl, thienyl, furyl, pyridyl, pyrazinyl, pyridazinyl
or pyrimidyl, [0033] where phenyl, naphthyl, thienyl, furyl,
pyridyl, pyrazinyl, pyridazinyl and pyrimidyl are unsubstituted or
substituted by 1, 2 or 3 substituents selected from the group
consisting of F, Cl, Br, I, CF.sub.3, OCF.sub.3, NO.sub.2, CN,
COMe, NH.sub.2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy
having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl,
methylsulfonyl and methylsulfonylamino; [0034] R(12) is alkyl
having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5 or 6
carbon atoms, aryl or heteroaryl, [0035] where aryl and heteroaryl
are unsubstituted or substituted by 1, 2 or 3 substituents selected
from the group consisting of F, Cl, Br, I, CF.sub.3, OCF.sub.3,
NO.sub.2, CN, COOMe, CONH.sub.2, COMe, NH.sub.2, OH, alkyl having
1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms,
dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
[0036] R(13) is C.sub.pH.sub.2p--R'(14); [0037] p is 0, 1, 2, 3, 4
or 5; [0038] R'(14) is cycloalkyl having 3, 4, 5 or 6 carbon atoms
tetrahydrofuranyl, tetrahydropyranyl, aryl or heteroaryl, [0039]
where aryl and heteroaryl are unsubstituted or substituted by 1, 2
or 3 substituents selected from the group consisting of F, Cl, Br,
I, CF.sub.3, OCF.sub.3, NO.sub.2, CN, COOMe, CONH.sub.2, COMe,
NH.sub.2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having
1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl
and methylsulfonylamino; [0040] R(15) is cycloalkyl having 3, 4, 5,
6, 7 or 8 carbon atoms; R(2) is hydrogen or alkyl having 1, 2, 3 or
4 carbon atoms; R(3) is alkyl having 3, 4, 5, 6 or 7 carbon atoms,
cycloalkyl having 3, 4, 5 or 6 carbon atoms, phenyl or naphthyl,
[0041] where phenyl or naphthyl are unsubstituted or substituted by
1, 2 or 3 substituents selected from the group consisting of F, Cl,
Br, I, CF.sub.3, OCF.sub.3, NO.sub.2, CN, COOMe, CONH.sub.2, COMe,
NH.sub.2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having
1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl
and methylsulfonylamino; R(4), R(5), R(6) and R(7) [0042] are,
independently of one another, selected from the group consisting of
hydrogen, F, Cl, Br, I, CF.sub.3, OCF.sub.3, OCHF.sub.2, NO.sub.2,
CN, COOMe, CONH.sub.2, COMe, NH.sub.2, OH, alkyl having 1, 2, 3 or
4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms,
dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
and the pharmaceutically acceptable salts thereof.
[0043] In one embodiment, compounds of formula I include those in
which: ##STR8## [0044] A is --C.sub.nH.sub.2n--; [0045] n is 0, 1,
2, 3, 4 or 5; [0046] O is oxygen; [0047] D is a bond or oxygen;
[0048] E is --C.sub.mH.sub.2m--; [0049] m is 0, 1, 2, 3, 4 or 5;
[0050] R(8) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or
C.sub.pH.sub.2p--R(14); [0051] p is 0, 1, 2, 3, 4 or 5; [0052]
R(14) is cycloalkyl having 3, 4, 5 or 6 carbon atoms, aryl or
heteroaryl, where aryl and heteroaryl are unsubstituted or
substituted by 1, 2 or 3 substituents selected from the group
consisting of F, Cl, Br, I, CF.sub.3, OCF.sub.3, NO.sub.2, CN,
COOMe, CONH.sub.2, COMe, NH.sub.2, OH, alkyl having 1, 2, 3 or 4
carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms,
dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
[0053] R(9) is hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon
atoms; [0054] R(10) is hydrogen, alkyl having 1, 2, 3 or 4 carbon
atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, aryl or
heteroaryl, [0055] where aryl and heteroaryl are unsubstituted or
substituted by 1, 2 or 3 substituents selected from the group
consisting of F, Cl, Br, I, CF.sub.3, OCF.sub.3, NO.sub.2, CN,
COOMe, CONH.sub.2, COMe, NH.sub.2, OH, alkyl having 1, 2, 3 or 4
carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms,
dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
[0056] R(11) is cycloalkyl having 3, 4, 5 or 6 carbon atoms, phenyl
or pyridyl, [0057] where phenyl and pyridyl are unsubstituted or
substituted by 1, 2 or 3 substituents selected from the group
consisting of F, Cl, Br, I, CF.sub.3, OCF.sub.3, NO.sub.2, CN,
COMe, NH.sub.2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy
having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl,
methylsulfonyl and methylsulfonylamino; [0058] R(12) is alkyl
having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5 or 6
carbon atoms, aryl or heteroaryl, [0059] where aryl and heteroaryl
are unsubstituted or substituted by 1, 2 or 3 substituents selected
from the group consisting of F, Cl, Br, I, CF.sub.3, OCF.sub.3,
NO.sub.2, CN, COOMe, CONH.sub.2, COMe, NH.sub.2, OH, alkyl having
1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms,
dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
[0060] R(13) is C.sub.pH.sub.2p--R'(14); [0061] p is 0, 1, 2, 3, 4
or 5; [0062] R'(14) is cycloalkyl having 3, 4, 5 or 6 carbon atoms,
tetrahydropyranyl, tetrahydrofuranyl, aryl or heteroaryl, where
aryl and heteroaryl are unsubstituted or substituted by 1, 2 or 3
substituents selected from the group consisting of F, Cl, Br, I,
CF.sub.3, OCF.sub.3, NO.sub.2, CN, COOMe, CONH.sub.2, COMe,
NH.sub.2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having
1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl
and methylsulfonylamino; R(2) is hydrogen or alkyl having 1, 2, 3
or 4 carbon atoms; R(3) is alkyl having 3, 4 or 5 carbon atoms,
phenyl, [0063] where phenyl is unsubstituted or substituted by 1, 2
or 3 substituents selected from the group consisting of F, Cl, Br,
I, CF.sub.3, OCF.sub.3, NO.sub.2, CN, COOMe, CONH.sub.2, COMe,
NH.sub.2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having
1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl
and methylsulfonylamino; R(4), R(5), R(6) and R(7) [0064] are,
independently of one another, selected from the group consisting of
hydrogen, F, Cl, Br, I, CF.sub.3, OCF.sub.3, OCHF.sub.2, NO.sub.2,
CN, COOMe, CONH.sub.2, COMe, NH.sub.2, OH, alkyl having 1, 2, 3 or
4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms,
dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
and the pharmaceutically acceptable salts thereof.
[0065] In another embodiment, compounds of formula I include those
in which: ##STR9## [0066] A is --C.sub.nH.sub.2n--; [0067] n is 0,
1, 2 or 3; [0068] O is oxygen; [0069] D is a bond or oxygen; [0070]
E is --C.sub.mH.sub.2m--; [0071] m is 0, 1, 2 or 3; [0072] R(8) is
hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; [0073] R(9) is
hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; [0074]
R(10) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or
cycloalkyl having 3, 4 or 5 carbon atoms, [0075] R(11) is
cycloalkyl having 3, 4, 5 or 6 carbon atoms, phenyl or pyridyl,
[0076] where phenyl and pyridyl are unsubstituted or substituted by
1, 2 or 3 substituents selected from the group consisting of F, Cl,
Br, CF.sub.3, OCF.sub.3, NO.sub.2, CN, COMe, OH, alkyl having 1, 2,
3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms,
dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
[0077] R(12) is alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl
having 3, 4 or 5 carbon atoms, aryl or heteroaryl, [0078] where
aryl and heteroaryl are unsubstituted or substituted by 1, 2 or 3
substituents selected from the group consisting of F, Cl, Br,
CF.sub.3, OCF.sub.3, NO.sub.2, CN, COOMe, CONH.sub.2, COMe, OH,
alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4
carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and
methylsulfonylamino; [0079] R(13) is C.sub.pH.sub.2p--R'(14);
[0080] p is 0, 1, 2, 3, 4 or 5; [0081] R'(14) is cycloalkyl having
3, 4, 5 or 6 carbon atoms, tetrahydrofuranyl, tetrahydropyranyl,
aryl or heteroaryl, [0082] where aryl and heteroaryl are
unsubstituted or substituted by 1, 2 or 3 substituents selected
from the group consisting of F, Cl, Br, CF.sub.3, OCF.sub.3,
NO.sub.2, CN, COOMe, CONH.sub.2, COMe, OH, alkyl having 1, 2, 3 or
4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms,
dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R(2) is hydrogen or alkyl having 1 or 2 carbon atoms; R(3) is alkyl
having 3, 4 or 5 carbon atoms, phenyl, [0083] where phenyl is
unsubstituted or substituted by 1, 2 or 3 substituents selected
from the group consisting of F, Cl, Br, CF.sub.3, OCF.sub.3,
NO.sub.2, COOMe, CONH.sub.2, COMe, OH, alkyl having 1, 2, 3 or 4
carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms,
dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R(4), R(5), R(6) and R(7) [0084] are, independently of one another,
selected from the group consisting of hydrogen, F, Cl, Br,
CF.sub.3, OCF.sub.3, OCHF.sub.2, NO.sub.2, CN, COOMe, CONH.sub.2,
COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1,
2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl
and methylsulfonylamino; and the pharmaceutically acceptable salts
thereof.
[0085] In yet another embodiment, compounds of formula I include
those in which: ##STR10## [0086] A is --C.sub.nH.sub.2n--; [0087] n
is 0, 1 or 2; [0088] O is oxygen; [0089] E is --C.sub.mH.sub.2m--;
[0090] m is 0 or 1; [0091] R(8) is hydrogen or alkyl having 1, 2, 3
or 4 carbon atoms; [0092] R(9) is hydrogen or alkyl having 1, 2, 3
or 4 carbon atoms; [0093] R(10) is hydrogen or alkyl having 1 or 2
carbon atoms [0094] R(11) is phenyl, [0095] where phenyl is
unsubstituted or substituted by 1, 2 or 3 substituents selected
from the group consisting of F, Cl, CF.sub.3, OCF.sub.3, CN, COMe,
OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3
or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and
methylsulfonylamino; R(2) is hydrogen; R(3) is alkyl having 3, 4 or
5 carbon atoms, phenyl, [0096] where phenyl is unsubstituted or
substituted by 1, 2 or 3 substituents selected from the group
consisting of F, Cl, CF.sub.3, OCF.sub.3, COOMe, CONH.sub.2, COMe,
OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3
or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and
methylsulfonylamino; R(4), R(5), R(6) and R(7) [0097] are,
independently of one another, selected from the group consisting of
hydrogen, F, Cl, CF.sub.3, OCF.sub.3, CN, COOMe, CONH.sub.2, COMe,
OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3
or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and
methylsulfonylamino; and the pharmaceutically acceptable salts
thereof.
[0098] In a further embodiment, compounds of formula I include
those in which: ##STR11## [0099] A is --C.sub.nH.sub.2n--; [0100] n
is 0, 1 or 2; [0101] D is a bond or oxygen; [0102] E is
--C.sub.mH.sub.2m--; [0103] m is 0 or 1; [0104] R(8) is hydrogen or
alkyl having 1, 2, 3 or 4 carbon atoms; [0105] R(9) is hydrogen or
alkyl having 1, 2, 3 or 4 carbon atoms; [0106] R(11) is phenyl or
pyridyl, [0107] where phenyl and pyridyl are unsubstituted or
substituted by 1, 2 or 3 substituents selected from the group
consisting of F, Cl, CF.sub.3, OCF.sub.3, CN, COMe, OH, alkyl
having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon
atoms, dimethylamino, sulfamoyl, methylsulfonyl and
methylsulfonylamino; [0108] R(12) is alkyl having 1, 2, 3 or 4
carbon atoms or cyclopropyl; R(2) is hydrogen; R(3) is alkyl having
3, 4 or 5 carbon atoms, phenyl, [0109] where phenyl is
unsubstituted or substituted by 1, 2 or 3 substituents selected
from the group consisting of F, Cl, CF.sub.3, OCF.sub.3, COOMe,
CONH.sub.2, COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms,
alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl,
methylsulfonyl and methylsulfonylamino; R(4), R(5), R(6) and R(7)
[0110] are, independently of one another, selected from the group
consisting of hydrogen, F, Cl, CF.sub.3, OCF.sub.3, CN, COOMe,
CONH.sub.2, COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms,
alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl,
methylsulfonyl and methylsulfonylamino; and the pharmaceutically
acceptable salts thereof.
[0111] In another embodiment, compounds of formula I include those
in which: ##STR12## [0112] A is --C.sub.nH.sub.2n--; [0113] n is 0,
1 or 2; [0114] D is a bond or oxygen; [0115] E is
--C.sub.mH.sub.2m--; [0116] m is 0 or 1; [0117] R(9) is hydrogen or
alkyl having 1 or 2 carbon atoms; [0118] R(10) is hydrogen or alkyl
having 1 or 2 carbon atoms; [0119] R(11) is cycloalkyl having 3, 4,
5 or 6 carbon atoms, phenyl, [0120] where phenyl is unsubstituted
or substituted by 1, 2 or 3 substituents selected from the group
consisting of F, Cl, CF.sub.3, OCF.sub.3, CN, COMe, OH, alkyl
having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon
atoms, dimethylamino, sulfamoyl, methylsulfonyl and
methylsulfonylamino; [0121] R(13) is C.sub.pH.sub.2p--R'(14);
[0122] p is 0, 1, 2, 3 or 4; [0123] R'(14) is aryl or heteroaryl,
[0124] where aryl and heteroaryl are unsubstituted or substituted
by 1, 2 or 3 substituents selected from the group consisting of F,
Cl, CF.sub.3, OCF.sub.3, CN, COOMe, CONH.sub.2, COMe, OH, alkyl
having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon
atoms, dimethylamino, sulfamoyl, methylsulfonyl and
methylsulfonylamino; R(2) is hydrogen; R(3) is alkyl having 3, 4 or
5 carbon atoms, phenyl, [0125] where phenyl is unsubstituted or
substituted by 1, 2 or 3 substituents selected from the group
consisting of F, Cl, CF.sub.3, OCF.sub.3, COOMe, CONH.sub.2, COMe,
OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3
or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and
methylsulfonylamino; R(4), R(5), R(6) and R(7) [0126] are,
independently of one another, selected from the group consisting of
hydrogen, F, Cl, CF.sub.3, OCF.sub.3, CN, COOMe, CONH.sub.2, COMe,
OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3
or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and
methylsulfonylamino; and the pharmaceutically acceptable salts
thereof.
[0127] Alkyl radicals and alkylene radicals may be straight-chain
or branched. This also applies to the alkylene radicals of formula
C.sub.nH.sub.2n, C.sub.mH.sub.2m and C.sub.pH.sub.2p. Alkyl
radicals and alkylene radicals may also be straight-chain or
branched if they are substituted or present in other radicals,
e.g., in an alkoxy radical or in a fluorinated alkyl radical.
Examples of alkyl radicals are methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl,
neopentyl, n-hexyl, and 3,3-dimethylbutyl, heptyl. The divalent
radicals derived from these radicals, e.g., methylene,
1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene,
2,2-propylene, 1,3-propylene, 1,1-butylene, 1,4-butylene,
1,5-pentylene, 2,2-dimethyl-1,3-propylene, 1,6-hexylene, etc., are
examples of alkylene radicals.
[0128] Cycloalkyl radicals may likewise be branched. Examples of
cycloalkyl radicals having 3 to 7 carbon atoms are cyclopropyl,
cyclobutyl, 1-methylcyclopropyl, 2-methylcyclopropyl, cyclopentyl,
2-methylcyclobutyl, 3-methylcyclobutyl, cyclopentyl, cyclohexyl,
2-methylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl,
cycloheptyl etc.
[0129] Suitable heteroaryl radicals include 2- or 3-thienyl, 2- or
3-furyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-,
4- or 5-pyrazolyl, 1,2,3-triazol-1-, -4- or 5-yl, 1,2,4-triazol-1-,
-3- or -5-yl, 1- or 5-tetrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or
5-isoxazolyl, 1,2,3-oxadiazol-4- or 5-yl, 1,2,4-oxadiazol-3- or
5-yl, 1,3,4-oxadiazol-2-yl or -5-yl, 2-, 4- or 5-thiazolyl, 3-, 4-
or 5-isothiazolyl, 1,3,4-thiadiazol-2- or -5-yl,
1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or 5-yl, 2-, 3-
or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, 3- or 4-pyridazinyl,
pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or
5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-indazolyl, 2-, 3-, 4-,
5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8- Isoquinolyl,
2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or
8-cinnolinyl, 2-, 3-, 5-, 6-, 7- or 8-quinoxalinyl, and 1-, 4-, 5-,
6-, 7- or 8-phthalazinyl. The corresponding N-oxides of these
compounds are also included, for example, 2-, 3- or 4-pyridyl
N-oxide.
[0130] Suitable heteroaromatic systems include thienyl, furyl,
pyrrolyl, imidazolyl, quinolyl, pyrazolyl, pyridyl, pyrazinyl,
pyrimidinyl and pyridazinyl.
[0131] Pyridyl refers to 2-, 3- and 4-pyridyl. Thienyl refers to
both 2- and 3-thienyl. Furyl refers to both 2- and 3-furyl.
[0132] Aryl includes phenyl and 2- or 3-naphthyl.
[0133] Monosubstituted phenyl radicals may be substituted in the 2,
3 or 4 position, disubstituted in the 2, 3, 2, 4, 2, 5, 2, 6, 3, 4
or 3, 5 positions, or trisubstituted in the 2, 3, 4, 2, 3, 5, 2, 3,
6, 2, 4, 5, 2, 4, 6 or 3, 4, 5 positions. This also applies
analogously to the N-containing heteroaromatic systems, the
naphthyl, thienyl or furyl radical.
[0134] In the case of di- or trisubstitution of a radical, the
substituents may be identical or different.
[0135] The compounds of formula I include those containing one or
more acidic or basic groups or one or more basic heterocycles, and
the corresponding physiologically or toxicologically tolerated
salts, in particular the pharmaceutically usable salts. Compounds
of formula I which carry acidic groups, e.g., one or more COOH
groups, may be provided as alkali metal salts, such as sodium or
potassium salts; alkaline earth metal salts, such as calcium or
magnesium salts; or ammonium salts, such as salts with ammonia or
organic amines or amino acids. For compounds of formula I in which
R3 is hydrogen, for example, deprotonation of the sulfonamide
moiety to yield a sodium salt is possible. Compounds of formula I
which contain one or more basic (i.e., protonatable) groups or
contain one or more basic heterocyclic rings can also be used in
the form of their physiologically tolerated acid addition salts
with inorganic or organic acids, such as hydrochlorides,
phosphates, sulfates, methanesulfonates, acetates, lactates,
maleates, fumarates, malates, gluconates, etc. If the compounds of
formula I contain both an acidic and a basic group, the compounds
may be provided as inert salts, e.g., betaines, in addition to the
other salt forms described above. Salts can be obtained from the
compounds of formula I by conventional processes, for example, by
combination with an acid or base in a solvent or dispersant or by
anion exchange from other salts.
[0136] With appropriate substitution, the compounds of formula I
may be present in stereoisomeric forms. If the compounds of formula
I contain one or more centers of asymmetry, they may, independently
of one another, have the S-configuration or the R-configuration.
The invention relates to the use of all possible stereoisomers
(e.g., enantiomers or diastereomers), and mixtures of two or more
stereomeric forms (e.g. enantiomers and/or diastereomers), in any
desired ratio. The invention thus relates, for example, to
enantiomers in enantiomerically pure form, both as levorotatory and
as dextrorotatory antipodes, and also in the form of mixtures of
the two enantiomers in different ratios or in the form of
racemates. The preparation of individual stereoisomers can be
effected, if desired, by separation of a mixture by conventional
methods or, for example, by stereoselective synthesis. In the
presence of one or more hydrogen atoms, the present invention also
comprises all tautomeric forms of the compounds of formula I.
[0137] The compounds of formula I can be prepared by various
chemical processes, some examples of which are outlined as scheme 1
or 2 below. The radicals R(1) to R(7) used herein are defined
above.
[0138] According to scheme 1, below, compounds according to the
invention can be prepared by first reacting an aminocarboxylic acid
of formula II, for example, with a sulfonyl chloride of formula
R(4)-SO.sub.2--Cl or a sulfonic acid anhydride, in a solvent such
as water, pyridine or ether, in the presence of a base. Suitable
bases include inorganic bases, such as sodium carbonate or
potassium hydroxide; or organic bases, such as pyridine or
triethylamine.
[0139] The resulting sulfonylaminocarboxylic acid of formula III
can then be activated to give an acid chloride, for example, by
reaction with a chlorinating agent such as phosphorus
pentachloride, phosphorus oxychloride or thionyl chloride, in an
inert solvent, followed by reaction with an amine of formula HR(1)
to give the title compounds of formula I. The activation of the
carboxylic acid group in the compound of formula III can also be
effected by numerous methods familiar to a person skilled in the
art, which are used in peptide chemistry for forming amide bonds;
for example, by conversion to a mixed anhydride or an activated
ester, or with the use of a carbodiimide, such as
dicyclohexylcarbodiimide.
[0140] The reaction of the activated sulfonylamino carboxylic acid
with an amine of formula H--R1 is typically carried out in an inert
solvent such as pyridine, tetrahydrofuran or toluene with or
without the addition of an inert base (for example, a tertiary
amine or pyridine). ##STR13##
[0141] Alternatively, as shown in scheme 2 below, it is also
possible to initially react the anhydrides of formula IV with an
amine of formula H--R1 to give an o-aminobenzamide of formula VII;
this aminobenzamide is then reacted with a sulfonyl chloride of
formula R(3)SO.sub.2Cl to obtain a compound of formula I. Another
possibility for preparing intermediates of formula VII in which
R(2) is hydrogen comprises the amidation of an o-nitrobenzoic acid
of formula V with an amine of formula HNR(1)R(2), followed by
reduction of the nitro group to the amine. ##STR14##
[0142] It may be appropriate in any of these procedures to
temporarily protect functional groups in the molecule during
certain reaction steps. Such protective group techniques are
familiar to the skilled worker. The selection of a suitable
protective group, and the processes for introducing and eliminating
them, are described in the literature and can be adapted where
appropriate to the individual compounds without difficulty.
[0143] The compounds of formula I and their physiologically
tolerated salts can be used on animals, preferably on mammals and,
in particular, on humans, as pharmaceuticals. Such pharmaceuticals
may comprise an individual compound of formula I or mixtures of two
or more such compounds in the form of pharmaceutical preparations.
The present invention also relates to compounds of formula I and
their physiologically tolerated salts for use as pharmaceuticals,
to their use in the therapy and prophylaxis of the pathological
states mentioned herein, and to their use for producing medicaments
therefor and medicaments with K.sup.+ channel-blocking effect. The
present invention further relates to pharmaceutical preparations
which comprise, as an active ingredient, an effective dose of at
least one compound of formula I and/or a physiologically tolerated
salt thereof. Such pharmaceutical preparations may further comprise
conventional pharmaceutically acceptable carriers and excipients.
The pharmaceutical preparations normally contain from 0.1 to 90% by
weight of the compounds of formula I and/or their physiologically
tolerated salts. The pharmaceutical preparations can be produced in
a manner known in the art. For example, the compounds of formula I
and/or their physiologically tolerated salts are mixed together
with one or more solid or liquid pharmaceutical carriers and/or
excipients and, if desired, with other active pharmaceutical
ingredients, into a suitable administration form or dosage form.
This dosage form may then be used as a pharmaceutical in human
medicine or veterinary medicine.
[0144] Pharmaceuticals which comprise compounds of formula I and/or
their physiologically tolerated salts can be administered orally,
parenterally, intravenously, rectally, by inhalation or topically.
The optimal administration will depend on the individual case,
e.g., the particular manifestation of the disease to be
treated.
[0145] Suitable pharmaceutically acceptable excipients are familiar
to the skilled worker. Such excipients include solvents, gel
formers, suppository bases, tablet excipients and other active
ingredient carriers, for example, antioxidants, dispersants,
emulsifiers, antifoams, flavor corrigents, preservatives,
solubilizers, agents to achieve a depot effect, buffer substances
or colorants.
[0146] The compounds of formula I can also be combined with other
active pharmaceutical ingredients to achieve an advantageous
therapeutic effect. Thus, in the treatment of cardiovascular
disorders, combinations with substances acting on the
cardiovascular system are possible and advantageous. Suitable
combination partners of this type include, for example, class I,
class II or class III antiarrhythmic agents, such as IK.sub.s- or
IK.sub.r channel blockers (e.g., dofetilide); antihypertensive
substances, such as ACE inhibitors (e.g., enalapril, captopril,
ramipril); angiotensin antagonists; K.sup.+ channel activators;
alpha- and beta-receptor blockers; sympathomimetic and adrenergic
compounds; Na.sup.+/H.sup.+ exchange inhibitors; calcium channel
antagonists; phosphodiesterase inhibitors; and other positively
inotropic substances, such as digitalis glycosides or
diuretics.
[0147] For oral use, the active compounds are mixed with additives
suitable for this purpose, such as carriers, stabilizers or inert
diluents, and converted by conventional methods into the suitable
administration forms such as tablets, coated tablets, hard gelatin
capsules, aqueous, alcoholic or oily solutions. Examples of inert
carriers which can be used include gum arabic, magnesia, magnesium
carbonate, potassium phosphate, lactose, glucose or starch,
especially corn starch. Preparation is possible in this connection
both as dry and as wet granules. Suitable oily carriers or solvents
include, for example, vegetable or animal oils, such as sunflower
oil or fish liver oil. Examples of suitable solvents for aqueous or
alcoholic solutions include water, ethanol or sugar solutions or
mixtures thereof. Further examples of excipients, also for other
administration forms, are polyethylene glycols and polypropylene
glycols.
[0148] For subcutaneous or intravenous administration, the active
compounds are converted into a solution, suspension or emulsion, if
desired, with the substances customary for this purpose such as
solubilizers, emulsifiers or other excipients. The compounds of
formula I and their physiologically tolerated salts can also be
lyophilized and the resulting lyophilizates used, for example, to
produce products for injection or infusion. Examples of suitable
solvents include water, physiological saline or alcohols, e.g.,
ethanol, propanol, glycerol, as well as sugar solutions such as
glucose or mannitol solutions, and mixtures of the various solvents
mentioned.
[0149] Suitable pharmaceutical formulations for administration in
the form of aerosols or sprays include, for example, solutions,
suspensions or emulsions of the active ingredients of formula I, or
their physiologically tolerated salts, in a pharmaceutically
acceptable solvent such as ethanol or water, or a mixture of such
solvents. The formulation can, if required, also contain other
pharmaceutical excipients such as surfactants, emulsifiers and
stabilizers, and a propellant gas. Such a preparation normally
contains the active ingredient in a concentration of about 0.1 to
10, optionally about 0.3 to 3, percent by weight.
[0150] The dosage of the active ingredient of formula I to be
administered or of the physiologically tolerated salt thereof
typically depends on the individual case and should be adapted in a
conventional way to the circumstances of the individual case for an
optimal effect. Thus, the dose depends on the frequency of
administration; the potency and duration of action of the compounds
employed for therapy or prophylaxis; the nature and severity of the
disease to be treated; the sex, age, weight and individual response
of the human or animal to be treated; and whether the therapy is
acute or prophylactic. The daily dose of a compound of formula I
for a patient weighing about 75 kg is from 0.001 mg/kg of
bodyweight to 100 mg/kg of bodyweight, optionally 0.01 mg/kg of
bodyweight to 20 mg/kg of bodyweight. The dose can be administered
in the form of a single dose or else be divided into a plurality of
doses, e.g., two, three or four single doses. In the treatment of
acute cases of cardiac arrhythmias, for example in an intensive
care ward, parenteral administration by injection or infusion may
also be advantageous, e.g., by a continuous intravenous
infusion.
EXAMPLES
[0151] List of abbreviations
DMAP 4-dimethylaminopyridine
DMF N,N-dimethylformamide
EDAC N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide
hydrochloride
EA ethyl acetate
HOBT 1-hydroxy-1H-benzotriazole
RT room temperature
THF tetrahydrofuran
BuLi butyllithium
General Method 1: Reaction of Anthranilic Acids with Sulfonyl
Chlorides to Give o-sulfonylaminobenzoic Acids (Analogous to the
Reaction Described in Organic Syntheses (1952), 32:8)
[0152] 1.2 mol of the appropriate sulfonyl chloride were added in
portions at 60.degree. C. to a solution of 260 g (2.4 mol) of
sodium carbonate and 1 mol of the appropriate anthranilic acid in
1.5 l of water. The reaction mixture was heated at 60-80.degree. C.
until the reaction was complete (about 1-6 h), adding further
sulfonyl chloride, if necessary. After cooling, the reaction
mixture was poured into 500 ml of 6 molar hydrochloric acid, and
the precipitate was filtered off with suction and dried in vacuo in
an oven at 45.degree. C. If the product did not result as crystals,
it was isolated by extraction with ethyl acetate.
Precursor 1 a: 2-(Toluene-4-sulfonylamino)benzoic acid
[0153] ##STR15##
[0154] 9.6 g of the title compound were obtained as a white solid
from 6.85 g of anthranilic acid and 10.5 g of para-toluenesulfonyl
chloride according to general method 1.
[0155] MS (ES): 293 (M+1).
Precursor 1 b: 2-Butylsulfonylamino-5-methylbenzoic acid
[0156] ##STR16##
[0157] 4.2 g of 2-butylsulfonylamino-5-methylbenzoic acid were
obtained from 5 g of 5-methylanthranilic acid and 6.2 g of
butanesulfonyl chloride according to general method 1.
[0158] MS (ES): 272 (M+1).
Precursor 1 c: 2-(4-Methoxybenzenesulfonylamino)-6-methylbenzoic
acid
[0159] ##STR17##
[0160] 1.6 g of the title compound were obtained as a viscous oil
from 1.5 g of 6-methylanthranilic acid and 2.3 g of
4-methoxybenzenesulfonyl chloride according to general method
1.
[0161] MS (ES): 323 (M+1).
[0162] The following further precursors were synthesized inter alia
according to general method 1: TABLE-US-00001 Precursor Structure
Mass (ES) 1d ##STR18## 312 (M + 1) 1e ##STR19## 326 (M + 1) 1f
##STR20## 310 (M + 1) 1g ##STR21## 306 (M + 1) 1h ##STR22## 306 (M
+ 1) 1i ##STR23## 308 (M + 1) 1j ##STR24## 278 (M + 1) 1k ##STR25##
326 (M + 1) 1l ##STR26## 312 (M + 1) 1m ##STR27## 326 (M + 1) 1n
##STR28## 292 (M + 1) 1o ##STR29## 322 (M + 1) 1p ##STR30## 376 (M
+ 1) 1q ##STR31## 356 (M + 1) 1r ##STR32## 322 (M + 1) 1s ##STR33##
322 (M + 1) 1t ##STR34## 352 (M + 1) 1u ##STR35## 272 (M + 1)
General Method 2: Conversion of Sulfonylaminobenzoic Acids into the
Corresponding Acid Chlorides
[0163] A) with Phosphorus Pentachloride
[0164] 8 mmol of the sulfonylaminobenzoic acid were suspended in 15
ml of dry toluene and, at room temperature, 9.6 mmol of phosphorus
pentachloride were slowly introduced. The mixture was stirred at
50.degree. C. for 3 h, and cooled to 0.degree. C., and the acid
chloride was filtered off with suction, washed with a little
toluene and dried in a vacuum oven at 45.degree. C.
Precursor 2 a: 2-(4-Toluenesulfonylamino)benzoyl chloride
[0165] ##STR36##
[0166] 7.5 g of the title compound were isolated as white solid
from 9.6 g of 2-(toluene-4-sulfonylamino)benzoic acid (precursor 1
a) and 8.3 g of phosphorus pentachloride. MS (ES, detected as
methyl ester after addition of methanol): 306 (M+1).
[0167] B) with Thionyl Chloride
[0168] 8 mmol of the sulfonylaminobenzoic acid were heated in 6 ml
of thionyl chloride at 60.degree. C. for 3 h, and concentrated, and
the residue was coevaporated twice with toluene.
Precursor 2 b: 2-(4-Methoxybenzenesulfonylamino)benzoyl
chloride
[0169] ##STR37##
[0170] 2.2 g of the title compound were obtained from 2.4 g of
2-(4-methoxybenzene-sulfonylamino)benzoic acid and 5 ml of thionyl
chloride.
[0171] MS (ES, detected as methyl ester after addition of
methanol): 322 (M+1).
[0172] The following further precursors were prepared inter alia
according to general method 2 (variant A or B): TABLE-US-00002 Mass
(ES after addition of methanol to the acid chloride) Detection of
the Precursor Structure methyl esters 2c ##STR38## 326 (M + 1) 2d
##STR39## 340 (M + 1) 2e ##STR40## 324 (M + 1) 2f ##STR41## 320 (M
+ 1) 2g ##STR42## 320 (M + 1) 2h ##STR43## 336 (M + 1) 2i ##STR44##
292 (M + 1) 2j ##STR45## 340 (M + 1) 2k ##STR46## 326 (M + 1) 2l
##STR47## 340 (M + 1) 2m ##STR48## 306 (M + 1) 2n ##STR49## 336 (M
+ 1) 2o ##STR50## 390 (M + 1) 2p ##STR51## 370 (M + 1) 2q ##STR52##
336 (M + 1) 2r ##STR53## 336 (M + 1) 2s ##STR54## 366 (M + 1) 2t
##STR55## 286 (M + 1) 2u ##STR56## 286 (M + 1)
General Method 3 A: Preparation of Secondary Amines by Reductive
Amination
[0173] 0.18 mmol of primary amine was dissolved in 200 ml of
methanol and, after addition of 0.09 mol of aldehyde, 0.18 mmol of
sodium cyanoborohydride and 0.18 mmol of glacial acetic acid,
stirred at room temperature for 6 h. The solution was concentrated,
taken up in ethyl acetate and washed twice with NaHCO.sub.3
solution. The organic phase was concentrated, and the residue was
distilled under high vacuum. In the case of involatile secondary
amines, volatile constituents were distilled off and the residue
was dissolved in ether/THF and, after addition of ethereal HCl
solution, the precipitated hydrochloride was filtered off with
suction, washed with ether and dried. The prepared secondary amines
were employed without further purification for the reactions with
the sulfonylaminobenzoyl chlorides or sulfonylaminobenzoic
acids.
Precursor 3 a: Benzyl(1-methyl-1H-imidazol-2-ylmethyl)amine
[0174] ##STR57##
[0175] The hydrochloride (20.5 g) was prepared from 19.4 g of
benzylamine and 10 g of 2-formyl-1-methylimidazole by the general
procedure.
[0176] MS (ES+): m/z=202 (M+1).
Precursor 3 b: Benzylpyridin-3-ylmethylamine
[0177] ##STR58##
[0178] The secondary amine (2.8 g) was prepared by the general
procedure from 4.32 g of 3-pyridylmethylamine and 2.12 g of
benzaldehyde after Kugelrohr distillation under 0.1 m bar at
130.degree. C.
[0179] MS (ES+): m/z=199 (M+1).
Precursor 3 c: Benzyl(3-imidazol-1-yl-propyl)amine
[0180] ##STR59##
[0181] The secondary amine (3.5 g) was prepared by the general
procedure from 12.5 g of 3-imidazol-1-ylpropylamine and 5.3 g of
benzaldehyde after Kugelrohr distillation under 0.1 m bar at
130.degree. C.
[0182] MS (ES+): m/z=216 (M+1).
[0183] The following further precursors were prepared inter alia by
general procedure 3A: TABLE-US-00003 Pre- cursor Structure Mass 3d
##STR60## 188 (M + 1) 3e ##STR61## 199 (M + 1) 3f ##STR62## 204 (M
+ 1) 3g ##STR63## 202 (M + 1) 3h ##STR64## 238 (M + 1) 3i ##STR65##
162 (M + 1) 3j ##STR66## 163 (M + 1) 3k ##STR67## 177 (M + 1) 3o
##STR68## 231 (M + 1) 3p ##STR69## 214 (M + 1) 3q ##STR70## 211 (M
+ 1) 3r ##STR71## 199 (M + 1)
General Method 3 B: Preparation of .alpha.-Branched Amines from
Ketones
[0184] A solution of 67 mmol of the appropriate ketone in 120 ml of
ethanol was added dropwise to a solution of 200 mmol of
hydroxylammonium chloride and 200 ml of sodium acetate in 120 ml of
water at 30.degree. C., and the mixture was heated at 60.degree. C.
until reaction was complete (1-3 h). After cooling, the reaction
mixture was diluted with water, and the precipitated oxide was
filtered off with suction or, if necessary, isolated by extraction.
The resulting product was dissolved in 100 ml of methanol, 100 ml
of THF and 10 ml of concentrated ammonia solution and hydogenated
in the presence of Raney nickel at RT under atmospheric pressure
until hydrogen uptake ceased. Removal of the catalyst by filtration
and concentration of the reaction mixture resulted in the
corresponding amine which was purified by chromatography, if
necessary.
Precursor 3 I: 1-Benzylpropylamine
[0185] ##STR72##
[0186] 4.5 g of the title compound were obtained from 10 g of
1-phenyl-2-butanone according to general method 3.
Precursor 3 m: 1-Pyridin-4-ylpropylamine
[0187] ##STR73##
[0188] 10.2 g of the title compound were obtained from 10 g of
4-propionylpyridine according to general method 3 B.
Precursor 3 n: 1-Pyridin-3-yl-propylamine
[0189] ##STR74##
[0190] 0.9 g of the title compound was obtained from 1 g of
3-propionylpyridine according to general method 3 B.
Precursor 3 s: 1-Cyclopropyl-1-phenylmethylamine hydrochloride
[0191] ##STR75##
a) N-(Cyclopropylphenylmethyl)formamide
[0192] 14.8 g (0.1 mol) of cyclopropyl phenyl ketone, 11.4 ml (0.3
mol) of formic acid and 20 ml (0.5 mol) of formamide were heated at
160.degree. C. for 18 h. After cooling, 100 ml of water were added
and the mixture was extracted 2.times. with 50 ml of ether each
time. The ether phase was washed with 50 ml of 10% Na.sub.2CO.sub.3
solution, dried over Na.sub.2SO.sub.4 and concentrated. 13.6 g
(77.4 mmol) of a yellow oil were obtained.
b) 1-Cyclopropyl-1-phenylmethylamine hydrochloride
[0193] 13.6 g (77.4 mmol) of N-(cyclopropylphenylmethyl)formamide
(see a) were heated to reflux in 100 ml of 2N HCl for 18 h. After
cooling, the mixture was extracted 2.times. with 50 ml of
dichloromethane each time, and the aqueous phase was concentrated.
The residue was taken up in 30 ml of 2-propanol, heated to boiling
and cooled in a refrigerator overnight. The crystals of
1-cyclopropyl-1-phenylmethylamine hydrochloride which had separated
out (3.85 g, 21 mmol) were filtered off with suction and dried in a
vacuum oven.
Precursor 3 t: Cyclopropylpyridin-2-yl-methylamine
hydrochloride
[0194] ##STR76##
a) Cyclopropylpyridin-2-ylmethyleneamine
[0195] 25 g (157.5 mmol) of 2-bromopyridine in 100 ml of diethyl
ether were added dropwise over the course of 20 min to 100 ml (160
mmol) of n-BuLi solution in 300 ml of diethyl ether at -70.degree.
C. The dark red solution was stirred for 5 h and then 8.8 g (131
mmol) of cyclopropanecarbonitrile in 100 ml of ether were added.
The mixture was stirred at -70.degree. C. for 30 min, warmed to
room temperature and stirred for a further 30 min. Then 15 g of
Na.sub.2SO.sub.4.times.10H.sub.2O were added, and stirring was
continued for 1 h. The red solution was mixed with
Na.sub.2SO.sub.4, filtered and concentrated. The product was
distilled in a Kugelrohr apparatus at 75.degree. C.-120.degree.
C./0.3 mbar as a pale yellow oil (18.6 g, 127 mmol) and was stored
at -18.degree. C.
b) Cyclopropylpyridin-2-ylmethylamine hydrochloride
[0196] 2.72 g (18.6 mmol) of cyclopropylpyridin-2-ylmethyleneamine
(see a) were dissolved in 35 ml of dry methanol. At 0.degree. C.,
0.69 g (18.6 mmol) of NaBH.sub.4 were added in portions. After 30
min at 0.degree. C., the mixture was stirred at room temperature
for 2 h and, after adjustment to pH 3 with 1 M HCl, the methanol
was stripped off in a rotary evaporator and the residue was
freeze-dried. 8.8 g of cyclopropylpyridin-2-ylmethylamine
hydrochloride mixed with inorganic salts and boric acid were
obtained.
Precursor 3 u: Cyclopropylpyridin-3-ylmethylamine hydrochloride
[0197] ##STR77##
a) Cyclopropylpyridin-3-ylmethyleneamine
[0198] 7.5 g (51 mmol) of the imine were isolated as a yellow oil
in accordance with the method for precursor 3 p starting from 8.8 g
(131 mmol) of cyclopropanecarbonitrile, 25 g (157.5 mmol) of
3-bromopyridine and 173 mmol of n-BuLi solution and after Kugelrohr
distillation (130.degree. C./0.2 mbar).
b) Cyclopropylpyridin-3-ylmethylamine hydrochloride
[0199] 16.6 g of cyclopropylpyridin-3-ylmethylamine hydrochloride
mixed with inorganic salts and boric acid were obtained in
accordance with the method for precursor 3 p starting from 7.5 g
(51.5 mmol) of imine (see a) and 1.9 g (51.4 mmol) of
NaBH.sub.4.
Precursor 3 v: 1-(5-Methylfuran-2-yl)propylamine
[0200] ##STR78##
[0201] 11.35 g (180 mmol) of sodium cyanoborohydride were
introduced in portions into 5 g (36 mmol) of
2-methyl-5-propionylfuran and 28.2 g (366 mmol) of ammonium acetate
in 300 ml of methanol with stirring and left to react at RT for 18
h. The mixture was substantially concentrated and, after addition
of 200 ml of dichloromethane, the organic phase was washed 3.times.
with 50 ml of NaHCO.sub.3 solution each time, dried over
Na.sub.2SO.sub.4 and concentrated. 3.9 g (28 mmol) of the amine
were obtained in the form of a pale yellow oil.
Precursor 3 w: 1-Phenylprop-2-ynylamine hydrochloride
[0202] ##STR79##
[0203] The compound was prepared in accordance with the method of
Bjorn M. Nilsson et al., J. Heterocycl. Chem. (1989), 26(2):269-75,
starting from 1-phenyl-2-propynyl alcohol by a Ritter reaction and
subsequent hydrolysis with hydrochloric acid.
Precursor 3x:
C-Cyclopropyl-C-(6-methoxypyridin-2-yl)methylamine
[0204] ##STR80##
a) Cyclopropanecarbaldehyde O-benzyloxime
[0205] 6.7 g (95.6 mmol) of cyclopropanecarbaldehyde were stirred
together with 15.3 g (95.6 mmol) of O-benzylhydroxylamine and 15.7
g (191.2 mmol) of sodium acetate in 250 ml of ethanol at room
temperature for 18 h and, after concentration, Na.sub.2SO.sub.4 was
added. The residue was extracted 3.times. with 50 ml of
dichloromethane each time, the organic phase was concentrated, and
the crude product was purified by chromatography on silica gel. 5 g
(28.6 mmol) of a colorless liquid were obtained.
b)
O-Benzyl-N-[cyclopropyl-(6-methoxypyridin-2-yl)methyl]hydroxylamine
[0206] 8.8 ml (22 mmol) of n-BuLi (2.5 M in toluene) were added to
3.76 g (20 mmol) of 2-bromo-6-methoxypyridine in 20 ml of THF at
-78.degree. C. After 30 min, this dark red solution was added to a
solution of 1.4 g (8 mmol) of cyclopropanecarbaldehyde
O-benzyloxime (see a) and 2.52 ml (20 mmol) of BF.sub.3 etherate in
40 ml of toluene which had been stirred at -78.degree. C. for 15
min. The mixture was stirred at -78.degree. C. for 4 h, slowly
warmed to RT and, after addition of water, made alkaline with
saturated Na.sub.2CO.sub.3 solution.
[0207] The organic phase was separated off, the aqueous phase was
extracted with toluene, and the combined organic phases were dried
over Na.sub.2SO.sub.4 and concentrated. The crude product was taken
up in 12 ml of acetonitrile, insolubles were removed, and the
product was isolated by preparative HPLC (650 mg, red oil).
C-Cyclopropyl-C-(6-methoxypyridin-2-yl)methylamine
[0208] 650 mg (2.3 mmol) of
O-benzyl-N-[cyclopropyl-(6-methoxypyridin-2-yl)methyl]-hydroxylamine
(see b) were dissolved in 18 ml of glacial acetic acid and diluted
with 18 ml of water. 3.3 g of zinc dust were added, and the
suspension was reacted in an ultrasonic bath for 24 h. The mixture
was filtered, washed with 50% acetic acid, and the filtrate was
partially evaporated and adjusted to pH 11 with saturated
Na.sub.2CO.sub.3 solution. It was extracted 3.times. with 100 ml of
dichloromethane each time, dried over Na.sub.2SO.sub.4 and
concentrated. 0.4 g (2.2 mmol) of the product was obtained in the
form of a dark red oil.
General Method 4 A: Preparation of 2-aminobenzamides from
2-nitrobenzoic acids
[0209] The appropriate 2-nitrobenzoic acid was initially reacted
analogously to general methods 2 and 5 with the respective amine to
give a 2-nitrobenzamide. Then 4 mmol of the 2-nitrobenzamide were
hydrogenated in 50 ml of THF and 50 ml of methanol in the presence
of a spatula tip of 10% palladium on carbon at RT under atmospheric
pressure. The catalyst was filtered off with suction, the reaction
mixture is concentrated, and the corresponding 2-aminobenzamide was
obtained.
[0210] The following precursor was, inter alia, synthesized in this
way: TABLE-US-00004 Precursor Structure Mass 4a ##STR81## 318 (M +
1)
General Method 4 B: Preparation of 2-aminobenzamides from isatoic
anhydride
[0211] A solution of 20 mmol of isatoic anhydride and 22 mmol of
the appropriate amine in 75 ml of DMF was heated at 60.degree. C.
until reaction was complete. 100 ml of water were added to the
reaction mixture, and the product was filtered off with suction or
isolated by extraction.
Precursor 4 b: (S)-2-Amino-N-(1-phenylpropyl)benzamide
[0212] ##STR82##
[0213] 3.4 g of the title compound were obtained from 3 g of
(S)-1-phenylpropylamine and 3.2 g of isatoic anhydride after 2 h at
60.degree. C. in accordance with general method 4 B.
General Method 5: Reaction of Sulfonylaminobenzoyl Chlorides with
Amines
[0214] 0.6 mmol of the particular sulfonylaminobenzoyl chloride was
added to a solution of 0.66 mmol of the particular amine and 0.9
mmol of triethylamine in 3 ml of methylene chloride, and the
mixture was stirred at room temperature overnight. The reaction
mixture was diluted with 5 ml of water and 10 ml of methylene
chloride, and the organic phase was washed successively with 1 M
hydrochloric acid solution and saturated sodium bicarbonate
solution. After drying over magnesium sulfate, the solution was
concentrated in vacuo, and the product was purified as necessary by
preparative HPLC or column chromatography.
Example 1
(S)-2-Phenylsulfonylamino-5-chloro-N-(1-phenylethyl)benzamide
[0215] ##STR83##
[0216] 61 mg of the title compound were obtained from
2-phenylsulfonylamino-5-chlorobenzoyl chloride and
S-(-)-1-methylbenzylamine in accordance with general method 5. MS
(ES+): m/z=415 (M+1).
Example 2
(R)-2-Phenylsulfonylamino-5-chloro-N-(1-phenylethyl)benzamide
[0217] ##STR84##
[0218] 160 mg of the title compound were obtained from
2-phenylsulfonylamino-5-chlorobenzoyl chloride and
R-(+)-1-methylbenzylamine in accordance with general method 5. MS
(ES+): m/z=415 (M+1).
Example 3
(S)-2-Phenylsulfonylamino-5-chloro-N-(1-phenylpropyl)benzamide
[0219] ##STR85##
[0220] 140 mg of the title compound were obtained from
2-phenylsulfonylamino-5-chlorobenzoyl chloride and
S-(-)-1-ethylbenzylamine in accordance with general method 5.
[0221] MS (ES+): m/z=429 (M+1).
Example 4
(R)-2-Phenylsulfonylamino-5-chloro-N-(1-phenylpropyl)benzamide
[0222] ##STR86##
[0223] 130 mg of the title compound were obtained from
2-phenylsulfonylamino-5-chlorobenzoyl chloride and
R-(+)-1-ethylbenzylamine in accordance with general method 5.
[0224] MS (ES+): m/z=429 (M+1).
Example 5
(S)-2-Phenylsulfonylamino-5-chloro-N-[1-(4-methoxyphenyl)ethyl]-benzamide
[0225] ##STR87##
[0226] 136 mg of the title compound were obtained from
2-phenylsulfonylamino-5-chlorobenzoyl chloride and
S-(-)-1-(4-methoxyphenyl)ethylamine in accordance with general
method 5. MS (ES+): m/z=445 (M+1).
Example 6
(R)-2-Phenylsulfonylamino-5-chloro-N-[1-(4-methoxyphenylethyl]-benzamide
[0227] ##STR88##
[0228] 112 mg of the title compound were obtained from
2-phenylsulfonylamino-5-chlorobenzoyl chloride and
R-(+)-1-(4-methoxyphenyl)ethylamine in accordance with general
method 5. MS (ES+): m/z=445 (M+1).
Example 7
2-Phenylsulfonylamino-5-chloro-N-(phenylpyridin-2-ylmethyl)benzamide
[0229] ##STR89##
[0230] 211 mg of the title compound were obtained from
2-phenylsulfonylamino-5-chlorobenzoyl chloride and
C-phenyl-C-pyridin-2-ylmethylamine in accordance with general
method 5. MS (ES+): m/z=478 (M+1).
Example 8
N-Benzyl-N-pyridin-3-ylmethyl-2-(toluene-4-sulfonylamino)benzamide
[0231] ##STR90##
[0232] 1.1 g of the title compound were obtained from 0.93 g of
2-para-toluenesulfonyl-aminobenzoyl chloride and 0.65 g of
benzylpyridin-3-ylmethylamine (precursor 3b) in accordance with
general method 5. The compound was isolated as a white salt after
addition of ethereal HCl solution.
[0233] MS (ES+): m/z=472 (M+1).
[0234] The following further examples inter alia were prepared in
accordance with general method 5: TABLE-US-00005 Example Structure
Mass (ES) 9 ##STR91## 425 (M + 1) 10 ##STR92## 443 (M + 1) 11
##STR93## 421 (M + 1) 12 ##STR94## 401 (M + 1) 13 ##STR95## 387 (M
+ 1) 14 ##STR96## 391 (M + 1) 15 ##STR97## 419 (M + 1) 16 ##STR98##
435 (M + 1) 17 ##STR99## 393 (M + 1) 18 ##STR100## 421 (M + 1) 19
##STR101## 425 (M + 1) 20 ##STR102## 353 (M + 1) 21 ##STR103## 373
(M + 1) 22 ##STR104## 407 (M + 1) 23 ##STR105## 429 (M + 1) 24
##STR106## 443 (M + 1) 25 ##STR107## 403 (M + 1) 26 ##STR108## 439
(M + 1) 27 ##STR109## 447 (M + 1) 28 ##STR110## 395 (M + 1) 29
##STR111## 489 (M + 1) 30 ##STR112## 475 (M + 1) 31 ##STR113## 477
(M + 1) 32 ##STR114## 489 (M + 1) 33 ##STR115## 472 (M + 1) 34
##STR116## 436 (M + 1) 35 ##STR117## 511 (M + 1) 36 ##STR118## 475
(M + 1) 37 ##STR119## 435 (M + 1) 38 ##STR120## 461 (M + 1) 39
##STR121## 503 (M + 1) 40 ##STR122## 489 (M + 1) 41 ##STR123## 505
(M + 1) 42 ##STR124## 450 (M + 1) 43 ##STR125## 559 (M + 1) 44
##STR126## 492 (M + 1) 45 ##STR127## 506 (M + 1) 46 ##STR128## 490
(M + 1) 47 ##STR129## 502 (M + 1) 48 ##STR130## 436 (M + 1) 49
##STR131## 450 (M + 1) 50 ##STR132## 488 (M + 1) 51 ##STR133## 453
(M + 1) 52 ##STR134## 409 (M + 1) 53 ##STR135## 440 (M + 1)
General Method 6: Reaction of Sulfonylaminobenzoic Acids with
Amines
[0235] 0.44 mmol of the particular amine was added dropwise to a
solution of 0.42 mmol of the appropriate sulfonylaminobenzoic acid,
0.44 mmol of HOBT and 0.44 mmol of EDAC in 5 ml of THF at 0.degree.
C., and the mixture was stirred at RT for 4 to 12 h. The reaction
mixture was diluted with EA and washed with dilute hydrochloric
acid and sodium bicarbonate solution. Drying over magnesium sulfate
and concentrating in vacuo resulted in the appropriate amide which
was purified as necessary by preparative HPLC.
Example 54
2-(Butylsulfonylamino)-N-cyclohexyl-5-methylbenzamide
[0236] ##STR136##
[0237] 184 mg of the title compound were obtained from 200 mg of
2-butylsulfonylamino-5-methylbenzoic acid (precursor 1 b) and
cyclohexylamine in accordance with general method 6. MS (ES+):
m/z=353 (M+1).
[0238] The following further examples inter alia were obtained in
accordance with general method 6: TABLE-US-00006 Example Structure
Mass 55 ##STR137## 375 (M + 1) 56 ##STR138## 409 (M + 1) 57
##STR139## 403 (M + 1) 58 ##STR140## 375 (M + 1)
General Method 7: Reaction of 2-aminobenzamides with sulfonyl
chlorides
[0239] A solution of 0.3 mmol of the appropriate sulfonyl chloride
in 2 ml of methylene chloride was added dropwise to a solution of
0.2 mmol of the appropriate 2-aminobenzamide (precursor 4) and 0.6
mmol of pyridine in 5 ml of methylene chloride at 0.degree. C., and
the mixture was stirred at RT overnight. The organic phase was
washed with water, dilute hydrochloric acid and sodium bicarbonate
solution, and the resulting crude product was purified if necessary
by preparative HPLC.
[0240] The following products inter alia were obtained in this way:
TABLE-US-00007 Example Structure Mass 59 ##STR141## 409 (M + 1) 60
##STR142## 409 (M + 1) 61 ##STR143## 445 (M + 1) 62 ##STR144## 445
(M + 1) 63 ##STR145## 425 (M + 1) 64 ##STR146## 425 (M + 1) 65
##STR147## 488 (M + 1) 66 ##STR148## 463 (M + 1) 67 ##STR149## 479
(M + 1) 68 ##STR150## 429 (M + 1) 69 ##STR151## 395 (M + 1) 70
##STR152## 488 (M + 1) 71 ##STR153## 438 (M + 1) 72 ##STR154## 486
(M + 1) 73 ##STR155## 361 (M + 1) 74 ##STR156## 389 (M + 1) 75
##STR157## 472 (M + 1) 76 ##STR158## 439 (M + 1) 77 ##STR159## 423
(M + 1)
[0241] The 3-methylbutylsulfonyl chloride required for example 74
was prepared from 3-methylbutyl bromide by reaction with ammonium
sulfite solution under reflux to give the sulfonic acid, followed
by chlorination with phosphorus pentachloride to give the sulfonyl
chloride.
[0242] The following compounds were additionally obtained
analogously to the above examples and by use of one or more of
general methods 1-7: TABLE-US-00008 Ex- ample Structure Mass 78
##STR160## 409 (M + 1) 79 ##STR161## 472 (M + 1) 80 ##STR162## 485
(M + 1) 81 ##STR163## 493 (M + 1) 82 ##STR164## 465 (M + 1) 83
##STR165## 474 (M + 1) 84 ##STR166## 478 (M + 1) 85 ##STR167## 425
(M + 1) 86 ##STR168## 460 (M + 1) 87 ##STR169## 486 (M + 1) 88
##STR170## 503 (M + 1) 89 ##STR171## 509 (M + 1) 90 ##STR172## 439
(M + 1) 91 ##STR173## 457 (M + 1) 92 ##STR174## 453 (M + 1) 93
##STR175## 451 (M + 1) 94 ##STR176## 407 (M + 1) 95 ##STR177## 431
(M + 1) 96 ##STR178## 455 (M + 1) 97 ##STR179## 455 (M + 1) 98
##STR180## 395 (M + 1) 99 ##STR181## 439 (M + 1) 100 ##STR182## 483
(M + 1) 101 ##STR183## 504 (M + 1) 102 ##STR184## 479 (M + 1) 103
##STR185## 439 (M + 1) 104 ##STR186## 443 (M + 1) 105 ##STR187##
395 (M + 1) 106 ##STR188## 447 (M + 1) 107 ##STR189## 511 (M + 1)
108 ##STR190## 497 (M + 1) 109 ##STR191## 493 (M + 1) 110
##STR192## 496 (M + 1) 111 ##STR193## 473 (M + 1) 112 ##STR194##
461 (M + 1) 113 ##STR195## 450 (M + 1) 114 ##STR196## 389 (M + 1)
115 ##STR197## 427 (M + 1) 116 ##STR198## 465 (M + 1)
[0243] The following further examples were prepared in accordance
with general method 5: TABLE-US-00009 Ex- ample Structure Mass (ES)
117 ##STR199## 504 (M + 1) 118 ##STR200## 487 (M + 1) 119
##STR201## 484 (M + 1) 120 ##STR202## 480 (M + 1) 121 ##STR203##
476 (M + 1) 122 ##STR204## 465 (M + 1) 123 ##STR205## 453 (M + 1)
124 ##STR206## 452 (M + 1) 125 ##STR207## 402 (M + 1) 126
##STR208## 436 (M + 1) 127 ##STR209## 432 (M + 1) 128 ##STR210##
385 (M + 1) 129 ##STR211## 432 (M + 1) 130 ##STR212## 409 (M + 1)
131 ##STR213## 452 (M + 1) 132 ##STR214## 402 (M + 1) 133
##STR215## 440 (M + 1) 134 ##STR216## 468 (M + 1) 135 ##STR217##
443 (M + 1) 136 ##STR218## 393 (M + 1)
[0244] The following further examples were prepared in accordance
with general method 6: TABLE-US-00010 Ex- ample Structure Mass (ES)
137 ##STR219## 406 (M + 1) 138 ##STR220## 404 (M + 1) 139
##STR221## 470 (M + 1) 140 ##STR222## 492 (M + 1) 141 ##STR223##
454 (M + 1) 142 ##STR224## 454 (M + 1) 143 ##STR225## 417 (M + 1)
144 ##STR226## 390 (M + 1) 145 ##STR227## 399 (M + 1)
[0245] The following further examples were prepared in accordance
with general method 7: TABLE-US-00011 Ex- ample Structure Mass (ES)
146 ##STR228## 377 (M + 1) 147 ##STR229## 377 (M + 1) 148
##STR230## 391 (M + 1) 149 ##STR231## 391 (M + 1) 150 ##STR232##
455 (M + 1) 151 ##STR233## 455 (M + 1)
Example 152
5-Hydroxy-N-(1-phenylpropyl)-2-(toluene-4-sulfonylamino)benzamide
[0246] ##STR234##
[0247] The compound was obtained from the compound of example 90 by
cleavage of the methyl ether with boron tribromide.
Example 153
Pharmacological Activity of the Prepared Compounds
[0248] Human Kv1.5 channels were expressed in Xenopus oocytes. For
this purpose, firstly ooytes were isolated from Xenopus laevis and
were defolliculated. Kv1.5-encoding RNA which had been synthesized
in vitro was then injected into these oocytes. After 1-7 days of
Kv1.5 protein expression, the Kv1.5 currents were measured on the
oocytes by the two-microelectrode voltage clamp technique. The
Kv1.5 channels were for this purpose usually activated with voltage
jumps lasting 500 ms to 0 mV and 40 mV. A solution of the following
composition flowed through the bath: NaCl 96 mM, KCl 2 mM,
CaCl.sub.2 1.8 mM, MgCl.sub.2 1 mM, HEPES 5 mM (titrated to pH 7.4
with NaOH). These experiments were carried out at room temperature.
The following were employed for data acquisition and analysis:
geneclamp amplifier (Axon Instruments, Foster City, USA) and MacLab
D/A converter and software (ADInstruments, Castle Hill, Australia).
The compounds of the invention were tested by adding them in
various concentrations to the bath solution. The effects of the
compounds were calculated as percentage inhibition of the Kv1.5
control current which was obtained when no compound was added to
the solution. The data were then extrapolated using the Hill
equation in order to determine the inhibitory concentrations
IC.sub.50 for the respective compounds.
[0249] The following IC.sub.50 values were determined in this way
for the compounds listed below: TABLE-US-00012 Example No.
IC.sub.50 [.mu.M] 1 5.5 2 8.2 3 2.8 4 4.1 5 4.5 6 8.2 7 5.1 8 0.9 9
4.9 10 2.5 11 8.0 12 5.4 13 10.0 14 8.5 15 7.8 16 6.4 17 7.5 18 6.7
19 4.2 20 7.7 21 5.2 22 4.8 23 5.0 24 3.0 25 3.4 26 0.6 27 5.6 28
3.2 29 5.1 30 0.7 31 2.6 32 8.5 33 6.5 34 3.1 35 2.0 36 2.0 37 1.9
38 1.6 39 >10 40 0.8 41 1.9 42 5.0 43 5.4 44 2.9 45 2.5 46 1.2
47 4.7 48 >10 49 6.3 50 0.7 51 3.6 52 3.0 53 2.5 54 4.0 55 4.6
56 10.0 57 5.0 58 >10 59 1.7 60 0.7 61 5.6 62 3.5 63 1.7 64 0.6
65 4.8 66 4.0 67 5.8 68 2.9 69 1.3 70 3.8 71 6.9 72 5.0 73 3.1 74
1.7 75 2.9 76 4.7 77 2.6 78 2.7 79 0.7 80 1.2 81 0.4 82 3.2 83 1.9
84 1.0 85 5.2 86 1.8 87 6.0 88 3.9 89 3.2 90 0.5 91 0.8 92 0.9 93
1.1 94 1.0 95 0.7 96 1.0 97 0.9 98 2.0 99 0.9 100 1.6 101 0.9 102
0.7 103 1.4 104 1.0 105 2.6 106 3.8 107 0.9 108 1.2 109 1.1 110 1.0
111 1.7 112 0.5 113 2.6 114 1.4 115 2.4 116 1.1 117 2.4 118 2.2 119
2.7 120 1.4 121 0.6 122 1.2 123 2.9 124 1.0 125 1.8 126 0.6 127 3.3
128 2.2 129 1.3 130 0.7 131 0.7 132 1.0 133 1.4 134 0.9 135 1.2 136
0.9 137 2.4 138 1.8 139 1.0 140 1.4 141 1.1 142 0.7 143 3.6 144 2.8
145 2.6 146 2.5 147 3.8 148 2.1 149 2.2 150 0.3 151 1.5 152 2.6
* * * * *